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Current Status of Genetic Testing for Colorectal Cancer Susceptibility

Current Status of Genetic Testing for Colorectal Cancer Susceptibility

This article is a comprehensive review of genetic testing for hereditary colorectal cancer detection. There is no longer any doubt that hereditary factors contribute to an increased risk of colon cancer. It remains to be seen how great their contribution is, how best to identify high-risk groups, and how best to care for carriers of the mutated genes. Approximately 25% of colorectal cancers occur in younger individuals or those with a family history of the disease, suggesting a heritable susceptibility.[1]

The recent identification and cloning of the genes responsible for familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC), along with other colon cancer genes, has led to the availability of genetic testing for hereditary colorectal cancer. Identifying individuals with FAP and HNPCC may result in individually tailored surveillance programs and consideration of prophylactic surgery to prevent the development of tumors.

Pathologic Evaluation

The clinical presentation and endoscopic appearance of FAP is fairly classical, and diagnosis is usually straightforward. Because the clinical findings of HNPCC can be subtle, an experienced gastrointestinal pathologist knowledgeable of the characteristics of HNPCC will help screen more patients for potential genetic testing. Colorectal cancer arising in HNPCC patients is typically characterized by mucinous or signet-ring cell carcinoma, poor cellular differentiation, and the presence of peritumoral lymphocytic infiltration.[2]

The histopathologic features of adenomas in HNPCC families usually include a villous component and show more high-grade dysplasia, supporting the hypothesis that they can progress to cancer more frequently and more rapidly then sporadic adenomas.[2] The fact that over 90% of HNPCC-related cancers demonstrate microsatellite instability suggests that screening tumors for high-frequency microsatellite instability is one way of selecting individuals for HNPCC testing.[1]

Indications for Genetic Testing

There must be a suspicion of hereditary colon cancer before it can be tested for, diagnosed, or treated surgically. Among the clues pointing to hereditary colon cancer are a family history, early age of cancer onset, multiple primary tumors, multifocal cancers, and cancer in combination with congenital abnormalities. Physicians continue to miss high-risk patients, despite the obvious phenotype of FAP patients. In 1990, Arvanitis et al demonstrated that the majority (59%) of patients with FAP die of metastatic colorectal cancer.[3] Genetic counseling should be offered to persons with an increased risk of FAP due to family history or the presence of multiple colonic polyps.

Genetic counseling of patients newly diagnosed with FAP and their families is essential. Patients with clinical FAP and no family history should also undergo genetic testing, as these patients represent the 30% with new germ-line mutations.[4] Attenuated FAP can be particularly difficult to diagnose clinically because affected patients may have only one or two small, right-sided adenomas, and colorectal cancer, when it develops, tends to occur 10 to 15 years later than classic FAP.

Determining when genetic testing is indicated for HNPCC is a far more difficult problem. Unlike FAP, patients with HNPCC do not have a unique phenotype. As in FAP, affected individuals should be tested first. The Amsterdam criteria have traditionally been used to determine eligibility for HNPCC testing; however, these guidelines have been criticized as being both too restrictive and too lax. The Amsterdam criteria ignore several important characteristics of HNPCC, such as the occurrence of extracolonic cancers. For the criteria to be met, a detailed family history is needed, and it is often unavailable.

Genetic counseling generally serves two functions: (1) to help the patient and family understand the medical and genetic information about FAP and HNPCC, and (2) to provide emotional and psychological support as the family copes with the new information and the burdens that such information can impose. The pretest counseling should include patient education on the risks, prophylactic procedures, and intervention options, and should address all potential consequences of genetic testing, including insurance and employability issues. Genetic testing for hereditary colon cancer is expensive and not uniformly covered by insurance companies. Furthermore, up-front copay costs and concern over insurance discrimination sometimes discourage high-risk patients from undergoing genetic testing.

Implications of Genetic Testing

Genetic testing results can alter the risk for index case family members from the standard 50% to essentially 0% or 100%. Once an index-affected individual is identified, presymptomatic genetic testing of at-risk family members can be performed quickly, accurately, and inexpensively. Family members testing negative do not have an increased risk of colon cancer and can avoid intense screening programs. Those testing positive are likely to improve their compliance for long-term screening programs and consider prophylactic surgery.

If the genetic test fails to identify the genetic alteration in the index person, no statement can be made regarding the individual gene carrier status of all family members. The specific gene mutation is undetectable in 20% of hereditary colon cancer families, and thus a negative genetic testing result could represent a false-negative.[5]


The goals of chemoprevention are to reduce cancer risk and improve quality of life. Potential benefits associated with the use of an active chemoprevention agent in hereditary colon cancer would be a decline in the frequency of surveillance procedures, surgical resections, cancer incidence, and cancer-related deaths.

Many investigators have examined the role of nonsteroidal anti-inflammatory drugs (NSAIDs) in the regression and prevention of adenomas in animal and human studies. Recent research has shown sulindac (Clinoril), a cyclooxygenase (COX)-2 inhibitor, to be quite effective at causing prevalent adenomas to regress or modulating proliferative markers, generally yielding noticeable results within 2 to 8 months after initiation.[6] The long-term efficacy of sulindac seems to require prolonged therapy, because adenomas have frequently recurred soon after discontinuation of the agent.[6] Several ongoing chemoprevention trials are looking at the role of selective COX-2 inhibitors in polyp regression in hereditary colon cancer patients.

In conclusion, the authors present an excellent overview of the current issues surrounding hereditary colorectal cancer. Patients at risk for this disease should undergo a comprehensive evaluation at institutions with dedicated geneticists, surgeons, gastroenterologists, social workers, and psychologists.


1. Terdiman JP, Conrad PG, Sleisenger MH: Genetic testing in hereditary colorectal cancer: Indications and procedures. Am J Gastroenterol 94(9):2344-2356, 1999.

2. Messerini L, Mori S, Zampi G: Pathologic features of hereditary non-polyposis colorectal cancer. Tumori 82:114-116, 1996.

3. Lynch HT, Smyrk T, Lynch J: An update of HNPCC (Lynch syndrome). Cancer Genet Cytogenet 93:84-99, 1997.

4. King JE, Dozois RR, Lindor NM, et al: Care of patients and their families with familial adenomatous polyposis. Mayo Clin Proc 75: 57-67, 2000.

5. Hahn M, Saeger HD, Schackert HK: Hereditary colorectal cancer: Clinical consequences of predictive molecular testing. Int J Colorectal Dis 14:184-193, 1999.

6. Hawk E, Lubet R, Limburg P: Chemoprevention in hereditary colorectal cancer syndromes. Cancer 86(S11):2551-2563, 1999.

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